Zonisamide is known as 1,2-benzisoxazole-3-methane sulfonamide or 3-(sulfamoylmethyl)-1,2-benzisoxazole. It has the following chemical formula: 
Zonisamide is currently available as an anti-epileptic agent which possesses anti-convulsant and anti-neurotoxic effects.
Several routes for zonisamide synthesis have been described in the literature. Two of these synthesis routes start from 4-hydroxy-coumarin via benzisoxazole acetic acid (hereinafter; BOA) and sodium salt of benzisoxazole methane sulfonic acid (hereinafter; BOS-Na).
Scheme 1 represents the first route for zonisamide synthesis. In this route, the zonisamide intermediate (BOA) is brominated followed by substitution of the bromine by sodium sulfite to give the advanced intermediate sodium salt of BOS (BOS-Na) as shown as follows: 
The sulfonation reaction of the zonisamide intermediate (i.e., BOA) with chlorosulfonic acid (in this case the reagent used also is the reaction solvent) gives the disulfonated-benzisoxazole-derivative (S-BOS) as the main reaction by-product. The synthetic method of the route shown in scheme 1 is a difficult method due to the great sensitivity of the reaction product.
The second method described in literature for zonisamide preparation includes the preparation of BOA starting from 4-hydroxy-coumarin, followed by the sulfonation reaction of BOA to BOS. The sulfonation reaction of the zonisamide intermediate (i.e., BOA) may be carried out with chlorosulfonic acid. The reagent chlorosulfonic acid is used in a large excess and it is also the reaction solvent. The reactions of this synthetic method are shown in scheme 2: 
When the reaction is conducted in chlorosulfonic acid, the sulfonation is not selective. Disulfonated-benzisoxazole derivateive (S-BOS) is a main product of the reaction.
The synthetic pathway via the sulfonation reaction of BOA comprises two steps lesser as compared to the synthetic pathway via the bromination reaction. In addition, the sulfonation reaction requires a large amount of chlorosulfonic acid which poses undesirable environmental problems.
U.S. Pat. No. 4,172,896 by Uno H. et al. (assigned to Dainippon Pharmaceutical Co.) describes the preparation of zonisamide using the sulfonating agent chlorosulfonic acid:dioxane complex. A similar reagent (SO3:dioxane complex) is known in the literature and was successfully used for the selective sulfonation of the aromatic ketones. Chlorosulfonic acid:dioxane is a selective sulfonating reagent and the disulfonated side products is obtained in a low quantity. The reaction is shown in scheme 3. 
Although the sulfonation method using chlorosulfonic acid:dioxane complex is selective, this method is not safe because of the serious environmental problem of the dioxane present in the reaction waste.
There is a continuous need to improve the sulfonation method that is both convenient and environmentally safe. The present invention provides an unexpected novel sulfonation process to prepare the intermediate of zonisamide.
Neither patents have characterized the existence of any crystalline forms of this product. There is a continuing need to investigate crystalline forms of BOS which can provide useful intermediates for zonisamide synthesis.
We found that the product of the sulfonation reaction (BOS) may be isolated as sulfonic acid type compound (BOS-H) or as its salt (metallic salts). Not depending on the product type form, the reaction mixture is usually treated with water allowing the isolation of the product with variable water content. These compounds have the tendency to give hydrates.
Furthermore, it is generally known that alkyl- and aryl-sulfonic acids and their salts can exist as hydrated form (C. M. Suter in “The Organic Chemistry of Sulfur”, J. Wiley, N.Y., 1946). The widely-known reagent p-toluene-sulfonic acid can exist as monohydrate. It is necessary to develop another method for preparation of the sodium salt of BOS.